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Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film.
Journal article

Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film.

  • Kiene K Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: Klara.Kiene@unibas.ch.
  • Hayasi N Kyukyu Pharmaceutical Co., Ltd., 32-7 Hibari, Imizu City, Toyama 939-0351, Japan. Electronic address: N-Hayasi@qqp.co.jp.
  • Burhenne J Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: Juergen.Burhenne@med.uni-heidelberg.de.
  • Uchitomi R Kyukyu Pharmaceutical Co., Ltd., 32-7 Hibari, Imizu City, Toyama 939-0351, Japan. Electronic address: R-Uchitomi@qqp.co.jp.
  • Sünderhauf C Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland. Electronic address: Claudia.Suenderhauf@usb.ch.
  • Schmid Y Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland. Electronic address: Yasmin.Schmid@usb.ch.
  • Haschke M Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland. Electronic address: Manuel.Haschke@insel.ch.
  • Haefeli WE Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: Walter-Emil.Haefeli@med.uni-heidelberg.de.
  • Krähenbühl S Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, 4031 Basel, Switzerland.
  • Mikus G Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: Gerd.Mikus@med.uni-heidelberg.de.
  • Inada H Kyukyu Pharmaceutical Co., Ltd., 32-7 Hibari, Imizu City, Toyama 939-0351, Japan. Electronic address: H-Inada@qqp.co.jp.
  • Huwyler J Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland. Electronic address: Joerg.Huwyler@unibas.ch.
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  • 2019-05-19
Published in:
  • European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. - 2019
Buccal film
CYP3A
Microdosing
Midazolam
Pharmacokinetics
Phenotyping
Administration, Buccal
Anti-Anxiety Agents
Area Under Curve
Cross-Over Studies
Cytochrome P-450 CYP3A
Drug Compounding
Drug Interactions
Female
Humans
Hypnotics and Sedatives
Male
Midazolam
Oral Mucosal Absorption
English Cytochrome P450 3A (CYP3A) isozymes metabolize about 50% of all marketed drugs. Their activity can be modulated up to 400-fold, which has great impact on individual dose requirements for CYP3A substrates. The activity of CYP3A can be monitored using the CYP3A substrate midazolam. To avoid pharmacological midazolam effects during phenotyping, a microdosing approach is preferred. However, the preparation of microdosed dosage forms remains a challenge. Fast dissolving buccal films are therefore proposed to facilitate this task. It was the aim of the present study to clinically evaluate a novel buccal film containing microdoses of midazolam for assessment of CYP3A activity. In a randomized, open-label crossover design, the pharmacokinetics of midazolam and its active hydroxy-metabolite, 1'‑OH‑midazolam, was assessed in 12 healthy volunteers after administration of single microdoses of midazolam (30 μg) as buccal film or buccal solution. The buccal film did rapidly disintegrate, was well tolerated, and no adverse events occurred. The film and the solution showed very similar midazolam plasma concentration-time profiles but were not bioequivalent according to EMA and FDA guidelines. For Cmax, AUC0-12h, and AUC0-∞ the geometric mean ratios of film to solution, with their 90% confidence intervals in parentheses, were 1.15 (1.00-1.32), 1.16 (1.04-1.28), and 1.19 (1.08-1.31), respectively. As a proxy for CYP3A activity, molar metabolic ratios of midazolam and 1'‑OH‑midazolam were analyzed over time, which revealed good correlations already 1 h or 2 h after application of the film or the solution, respectively. The tested midazolam buccal film is a convenient dosage form that facilitates administration of a phenotyping probe considerably and may potentially be used in special patient populations such as pediatric patients. Clinical Trials.gov Identifier: NCT03204578.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/232508
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